Nearly 16.3 million patients in the United States have coronary heart disease (CHD), a condition associated with significant morbidity and mortality and high healthcare costs. There is an urgent need to identify biomarkers that predict adverse outcomes in patients with CHD to enable reliable prognostication, insights into pathophysiology, and discovery of new targets for therapy. Validated prognostic markers will facilitate management of CHD since physicians often face complex choices concerning the range of therapies for secondary prevention and the need for coronary revascularization. The goal of this application is to investigate whether plasma levels of osteoprotegerin (OPG) predict adverse outcomes (fatal and nonfatal myocardial infarction, ischemic stroke and heart failure) in patients participating in the Prevention of Events with Angiotensin-Converting Enzyme Inhibitor Therapy (PEACE) trial. OPG is a glycoprotein belonging to the tumor necrosis factor (TNF) receptor superfamily, and a soluble decoy receptor for the receptor activator of nuclear factor-B ligand (RANKL) and TNF-related apoptosis inducing ligand (TRAIL). It has been implicated in maintenance of endothelial cell integrity, inflammatory response, and vascular calcification. Circulating levels of OPG are easily measured, in contrast to RANK and RANKL that are expressed locally in the cardiac and vascular tissue. We hypothesize that an upregulated OPG/RANK/RANKL system is a marker of adverse outcomes in patients with stable CHD. Furthermore, OPG-RANKL pathway may be target for drug therapy to improve outcomes in patients with CHD. The proposed research will leverage the infrastructure of the PEACE trial and our experience in biomarker research including validation of immunoassays. Using an immunoassay previously established in the applicant's laboratory, we will measure plasma OPG in 3634 patients with stable CHD participating in the PEACE trial and with available baseline plasma samples. We will investigate whether plasma levels of OPG are associated with adverse outcomes (fatal and nonfatal myocardial infarction, ischemic stroke, and heart failure) independent of age, sex, ethnicity, conventional risk factors, and estimated glomerular filtration rate. In addition, we will assess whether any association of plasma OPG with adverse events is independent of circulating levels of C-reactive protein and NT-proBNP. Incremental predictive utility will be assessed by the c-statistic, net reclassification index, and integrated discriminaton improvement (IDI).